Renal failure patients often show alterations in drug disposition as compared to non-renal failure patients. These alterations are not always predictable which can cause problems in optimizing drug therapy in renal failure patients. This project will investigate the different mechanisms whereby drug disposition is altered in these patients. Pharmacokinetic studies will be performed in uremic and normal animals, in the presence and absence of infused drug metabolites. Liver and kidney perfusions will be carried out to localize and identify particular mechanisms for drug disposition alterations. Pharmacokinetic studies will also be performed in normal volunteers and in patients with decreased renal function under treatment with the investigated drugs. Total and unbound plasma concentrations and urinary excretion of drug and drug metabolites will be determined simultaneously by testing the renal function.